Project 1 (P1) provides molecular tests at the cell type-specific level for the following aspects of the Central Hypothesis: 1) a core cortical pathology in schizophrenia affects layer 3 pyramidal cells, and 2) the impact of this pathology on gene expression is moderated by factors that differ across cortical regions. Layer 3 pyramidal cells will be collected using laser microdissection in postmortem samples from subjects with schizophrenia or schizoaffective disorder and healthy comparison subjects (Aim 1). Within-region analyses will inform on the cell autonomous pathology of layer 3 pyramidal cells in schizophrenia. Across-region analyses will characterize molecular regional specificities in control subjects and how they impact the pathology of layer 3 pyramidal cells in schizophrenia. A secondary goal is to gain insight into potential molecular targets to restore functional balance along the visual working memory and attention network. Accordingly, since layer 3 pyramidal cell alterations are predicted to induce transcriptional responses in the parvalbumin (PV)-containing GABA neurons that they innervate, similar analyses will be performed in PV neurons (Aim 2). To provide a comprehensive molecular perspective on coordinated local circuit alterations, expression of genes (mRNA) and gene regulatory micro-RNAs (miRNA) will be investigated in parallel (Aims 1-2) and biological modules implicated in healthy control and pathological conditions will be identified by changes in coordinated expression across cell types, regions and cohorts (Aim 3). Results from PI will inform all other Center projects on the molecular and cellular bases in regards to the Central Hypothesis that regional differences moderate the serverity of layer 3 PC alterations in schizophrenia. PI will also provide molecular leads for protein marker studies in P2, and for layer 3 PC regional differences in electrophysiological properties in P3. Together Projects 1-3 will provide the molecular, cellular and circuitry bases for the functional connectivity studies in monkey (P4), and in imaging studies of healthy controls and subjects with schizophrenia (P5). RELEVANCE (See instructions): This project will characterize at the cellular level the core molecular pathology in cortical layer 3 pyramidal cells in schizophrenia and determine how this pathology is moderated by factors that include regional specificity in the expression of mRNAs and miRNA regulatory elements. Project 1 will also provide insight into potential targets to restore functional balance along the visual cortical network.